The overall goal of the proposed studies is to determine mechanisms by which acute ethanol exposure prior to thermal injury diminishes the magnitude of cell mediated immunity to a greater extent than observed following thermal injury alone. Nearly 100,000 people each year are admitted to hospitals due to burn injury and about half of those patients are reported to have been drinking alcohol. Alcohol exposure is not only a risk factor for the events that lead up to the fire related accidents, it also leads to increased morbidity and mortality among burned patients. Burn patients who had moderate to high blood alcohol levels on admission stay in the hospital twice as long, required 60% more surgical procedures and more rigorous antibiotic therapy, and are twice as likely to suffer serious infectious complications than burn patients not exposed to alcohol having identical burn injuries. These complications arise in alcohol exposed individuals because of ethanol mediated effects on cell mediated immune functions. The investigators hypothesize that the level of circulating ethanol at the time of thermal injury dictates the degree of immune dysfunction. The proposed studies are designed to explore mechanisms by which alcohol alters mitogen-induced splenocyte proliferation and contact hypersensitivity responses in thermally injured mice given different levels of ethanol at various intervals prior to injury. Since macrophages from these mice suppress the function of lymphocytes, studies will examine the production of macrophage-derived immunomodulatory mediators, including interleukin-6 (IL-6) and transforming growth factor -beta (TGFB). If it is demonstrated that acute ethanol exposure prior to thermal injury alters splenocyte proliferation by increasing the production of IL-6 and/or TGFB, then further studies will 1) define the cells responsible for the aberrant production of these mediators and 2) use neutralizing antibodies directed against those cytokines in vivo and in vitro to determine if normal immune cell function can be restored. Since glucocorticoids are elevated after stress (such as alcohol exposure and burn injury) and can alter cytokine production leading to immunosuppression, further investigation will be directed at examining whether alcohol exposure prior to thermal injury alters the kinetics or magnitude of circulating corticosterone. In the event that the PI observe elevated plasma glucocorticoid levels which correlate with depressed immune function, then they will attempt to block the actions of glucocorticoids in vivo using the glucocorticoid receptor antagonist, RU486. At the present time, it is unclear how acute ethanol exposure affects cell mediated immunity and overall rates of mortality and morbidity among burned individuals. Studies such as those described herein will yield valuable information regarding the mechanisms by which acute ethanol exposure adversely affects immune cell function in the burned individual. In addition, these studies may also provide information necessary for improving treatments and therapies for the burned, immunosuppressed patient.